Heteropentacyclic nucleosides (e.g., ribavirin, showdomycin and pyrazomycin) are agents having known pharmacologic activities. The heteropentacyclic nucleoside ribavirin, for example, can inhibit the replication of both RNA and DNA viruses. Showdomycin and pyrazomycin are heteropentacyclic nucleosides known to have antibiotic activity.
Some drugs in the heteropentacyclic nucleoside class are extensively metabolized via first-pass hepatic metabolism. In addition, some drugs in this class (and ribavirin in particular) can cause hemolytic anemia, a serious and often life-threatening condition. Anemia can occur when ribavirin diffuses into and accumulates within erythrocytes, due to an inability of erythrocytes to hydrolyze (dephosphorylate) the drug. Erythrocytes are unable to hydrolyze the drug because they lack phosphatases with the result that the ribavirin phosphate concentration can reach a level that is 60- to 100-fold higher than its plasma concentration. At these high levels, ribavirin phosphate can deplete intracellular ATP, impair ATP-dependent oxidative respiratory pathway, damage erythrocyte membrane integrity and eventually cause hemolytic anemia. Although these effects are reversible and may be mitigated by removing the drug, reducing the drug or administering erythropoietin, it would be advantageous to be able to administer a compound having ribavirin and other heteropentacyclic nucleosides without regard for these or other undesired effects.
The present invention seeks to address these and other needs in the art.